We plan to identify the immunogenetic, cellular and regulatory mechanisms involved in the immunologic adaptation of the recipient to donor HLA disparities. In human transplantation, the life-long use of immunosuppressive drugs has been necessary but is also associated with numerous side effects. Previous studies indicate some kidney recipients demonstrate specific proliferative unresponsiveness in MLC to donor cells posttransplant. Those patients who develop donor antigen-specific hyporeactivity may be candidates for withdrawal or reduction of maintenance immunosuppressive therapy. We will determine what proportion of CSA- treated recipients have developed in vitro donor antigen-specific hyporeactivity. Our preliminary studies, using a combination of donor cells and homozygous typing cells defining the HLA-Dw specificities of the donor cells (in MLR), have identified in vitro donor antigen-specific hyporeactivity for 34% of the CSA-treated haploidentical living related donor (LRD) recipients. This subgroup had lower serum creatinines at 1 and 2 years posttransplant and had fewer rejection episodes after 6 months than those recipients who did not demonstrate in vitro donor antigen-specific hyporeactivity. In addition, there have been no graft losses in the hyporesponsive group vs. 3 (11%) in the non-hyporesponsive group. The exact mechanisms involved in the development of donor antigen-specific hyporeactivity are not known. We will focus on the study of the cellular basis and mechanisms involved in the development of the donor antigen specific hyporeactivity. In our preliminary studies, we observed an increased percentage of HLA-DQ-directed clones in the patient anti-donor priming combinations of 2 patients who demonstrated in vitro donor antigen- specific hyporeactivity were consistent with increased suppressor cell phenotypes. Finally, we will determine whether the development of donor antigen-specific hyporeactivity predicts successful withdrawal or tapering of immunosuppression. Our goal is to reduce the side effects of immunosuppression by providing immunologically based-criteria for the selection of patients who can be successfully withdrawn or tapered from immunosuppression.